rs767341738

Positions:

• chr10-18539273-GT-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_201596.3(CACNB2):​c.1534del​(p.Ser512LeufsTer57) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CACNB2 NM_201596.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -2.21

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1534del	p.Ser512LeufsTer57	frameshift_variant	14/14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1372del	p.Ser458LeufsTer57	frameshift_variant	13/13	ENST00000377329.10	NP_963884.2
LOC124902386	XR_007062076.1	n.3del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1534del	p.Ser512LeufsTer57	frameshift_variant	14/14	1	NM_201596.3	ENSP00000320025
CACNB2	ENST00000377329.10	c.1372del	p.Ser458LeufsTer57	frameshift_variant	13/13	1	NM_201590.3	ENSP00000366546
	ENST00000425669.1	n.402del		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251384 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2017

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Ser512fs in CACNB2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 512 and leads to a premature termination codon 57 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. LoF not a known disease mechanism. In summary, the clinical significance of the p.Ser512fs variant is uncertain. -

Brugada syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 22, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.1372delT variant, located in coding exon 13 of the CACNB2 gene, results from a deletion of one nucleotide at nucleotide position 1372, causing a translational frameshift with a predicted alternate stop codon (p.S458Lfs*57). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of CACNB2 has not been clearly established as a mechanism of disease. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767341738; hg19: chr10-18828202;